Glutamatergic cortical inputs to the nucleus accumbens (NAc) and caudate-putamen (CPu) control motivated behaviors directly influenced by reward and by addictive drugs that can produce long-term changes in synaptic efficacy. Prefrontal and anterior cingulate cortical afferents target striatal spiny GABAergic neurons containing functionally opposed opioid (enkephalin and dynorphin) peptides. These neurons and/or afferent terminals also express all known subtypes of opioid receptors as well as cannabinoid 1 (CB1) receptors activated by endogenous cannabinoids and by Delta-9-tetrahydrocannabinol (THC), the primary psychoactive substance in marijuana. Thus, the identification of pre-(axonal) and/or post- (dendritic) synaptic neuronal, or possibly glial sites for opioid and cannabinoid receptor activation is crucial for understanding the mechanisms of drug addiction. Many of these sites were established for the morphine-binding mu-opioid receptor during the current funding period by using quantitative high-resolution electron microscopic immunocytochemistry. This method will be used for determining the location of the CB1 receptor within the striatal circuitry, specifically as related to functional interactions with either the mu-opioid or ionotropic (AMPA and NMDA) glutamate receptor subunits, whose plasma membrane distributions are highly regulated by synaptic activity and are potentially altered by chronic morphine administration. Specific Aims 1-3 will test the hypothesis that CB1 receptors in both the NAc and CPu are strategically positioned for involvement in (1) modulation of glutamatergic corticostriatal transmission, (2) regulation of dendritic plasma membrane expression of both mu-opioid and ionotropic glutamate receptor subunits, and (3) differential control of the output of enkephalin and dynorphin containing projection neurons. Aims 1-3 will be conducted mainly in male rats, but also will use wild type and CB1 (-/-) mice that are specifically deficient in opiate reward. Aim 4 will test the hypotheses that in the NAc shell and CPu of rat brain, (1) chronic, intermittent morphine produces changes in the synaptic availability of AMPA (GluR1 and GluR2) and/or NMDA (NR1 and NR2) glutamate receptor subunits, and (2) these changes depend, in part, on mu-opioid and CB1 receptor distributions. Together, the results will have far reaching implications for understanding drug cross-sensitization and devising new treatment strategies for opiate addiction.